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• Proteogenomic Characterization Unveils Biomarkers Associated With Chemoresistance in Muscle Invasive Bladder Cancer

  Cisplatin-based neoadjuvant chemotherapy (NAC) combined with radical cystectomy has been used as a standard of care for patients with clinically non-metastatic muscle invasive urothelial bladder cancer, but 40-50% patients will benefit from the treatment. Molecular subtypes of muscle invasive bladder cancer (MIBC) provide a possible biomarker roadmap that may help identify patients who may or may not respond to NAC. Recently, by integrating Mass Spectrometry-based proteomics, proteogenomic studies from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) have demonstrated the potential of this approach in prioritizing candidate driver genes and facilitating understanding of the chemotherapy resistance mechanisms. To demonstrate the proteogenomic workflow for investigating the mechanisms underlying chemotherapy resistance in MIBC, we conducted proteogenomic characterization of 46 pre- and 14 post- treatment tumors, including whole exome sequencing (WES), mRNA sequencing, Tandem Mass Tag (TMT)-proteomics, or TMT-phosphoproteomic. These samples were selected from an initial cohort of 143 MIBC tissues and filtered by tumor purity, clinical history, pathological response, and proteomic quality control metrics. The final cohort comprised samples from 53 patients, including 45 with both genomic and proteomic data and 8 with genomic data only.Our multi-omics-based clustering reveals subtypes associated with chemotherapy sensitivity. Protein abundance of a short isoform of ATAD1 and RAF family proteins were identified as biomarkers of chemosensitivity which highlights the importance of proteomics data. Integration of proteomic and phosphoproteomic data reveals Wnt signaling via GSK3B-S9 phosphorylation and the JAK/STAT pathway as potential targets to overcome chemoresistance. Correlations between PD-L1 and TROP-2/NECTIN-4 indicate an additive benefit of combination therapy targeting these proteins. Our data analysis clearly demonstrates that proteogenomic plays an important role in uncovering potential resistance mechanisms that operate only at protein and Post-Translational Modification (PTM) levels. Proteomics data can be accessed through PRIDE with ID PXD060290. RNA-seq and whole-exome sequencing (WES) FASTQ files are archived in the dbGaP database.

  Study phs004049

• Genomic features of Helicobacter pylori-na��ve diffuse-type gastric cancer.

  Helicobacter pylori (HP) is a major etiologic driver of diffuse-type gastric cancer (DGC). However, improvements in hygiene have led to an increase in the prevalence of HP-na��ve DGC; that is, DGC that occurs independent of HP. Although multiple genomic cohort studies for gastric cancer have been conducted, including studies for DGC, distinctive genomic differences between HP-exposed and HP-na��ve DGC remain largely unknown. Here, we employed exome and RNA sequencing with immunohistochemical analyses to perform binary comparisons between 36 HP-exposed and 27 HP-na��ve DGCs from sporadic, early-stage, and intramucosal or submucosal tumor samples. Among the samples, 33 HP-exposed and 17 HP-na��ve samples had been preserved as fresh-frozen samples. HP infection status was determined using stringent criteria. HP-exposed DGCs exhibited an increased single nucleotide variant burden (HP- exposed DGCs; 1.97 [0.48���7.19] and HP-na��ve DGCs; 1.09 [0.38���3.68] per megabase; p=0.0003) and a higher prevalence of chromosome arm-level aneuploidies (p<0.0001). CDH1 was mutated at similar frequencies in both groups, whereas RHOA���ARHGAP pathway misregulation was exclusive to HP-exposed DGCs (p=0.0167). HP-exposed DGCs showed gains in chromosome arms 8p/8q (p<0.0001), 7p (p=0.0035) and 7q (p=0.0354), and losses in 16q (p=0.0167). Immunohistochemical analyses revealed a higher expression of intestinal markers such as CD10 (p<0.0001) and CDX2 (p=0.0002) and a lower expression of the gastric marker, MUC5AC (p=0.0305) among HP-exposed DGCs. HP-na��ve DGCs, on the other hand, had a purely gastric marker phenotype. This work reveals that HP-na��ve and HP-exposed DGCs develop along different molecular pathways, which provide a basis for early detection strategies in high incidence settings.

  Study JGAS000575

• Local In Time Statistics for processual research

  Background: Functional genomics in a processual analysis cover the time-dependent changes in transcriptomics and epigenetics before diagnosis of a disease, reflecting the changes in both life style and disease processes. The aim of this paper is to explore the dynamic, time-dependent mechanisms of the metastatic processes, using blood transcriptomics and including time in a continuous manner. For achieving this goal we develop new statistical methods based on statistics that are local in time. Methods: The new statistical method, Local In Time Statistics (LITS), is based on calculating statistics in moving windows and randomization. The method has been tested for the analysis of a dataset that collectively provides information on the blood transcriptome up to eight years before breast cancer diagnosis. The dataset from the NOWAC Post-genome Cohort consists of 467 case-control pairs matched on birth year and time of blood sampling. The data for a pair is the difference in log2 gene expression between the case and control. The stratified analyses are based on important biological differences like metastatic versus non-metastatic cancer, and the mode of cancer detection, i.e. screening detected versus clinically detected cancers. The dataset was used for examining whether the gene expression profile varies between cases and controls, with time, or between cases with and without metastases. Results: The null hypotheses of no differences between cases and controls, no time-dependent changes, and no differences between different strata were all rejected. For screening detected cancers the probability of correct prediction of metastasis status was best in year 1 before diagnosis compared to year 3 and 4 before diagnosis for clinically detected cancers. The predictor was not very sensitive to the number of genes included.Conclusions: Using a new statistical method, LITS, we have demonstrated time-dependent changes of the blood transcriptome up to eight years before breast cancer diagnosis.

  Study EGAS00001002520

• High density copy number analysis and whole exome sequencing of unselected chronic lymphocytic leukemia cases and of paired chronic lymphocytic leukemia and Richter Syndrome cases

  Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance. Genetic Lesions associated with Chronic Lymphocytic Leukemia transformation to Richter Syndrome Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell type (DLBCL). The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator locus is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

  Study phs000364

• GA4GH

  Standards The EGA is a long-standing supporter of the Global Alliance for Genomics & Health (GA4GH) to enhance responsible sharing of human genetic data through the development of interoperable global standards for human data access. The EGA is one of the founding GA4GH Driver Projects and has contributed to the development and implementation of several GA4GH standards and APIs. Below is a list of the GA4GH standards and APIs that are currently available or planned for implementation at EGA. TechnicalStandards Purpose SpecificationVersion SupportedVersion Implementation Large Scale Genomics htsget A protocol for secure, efficient, and reliable access to sequencing read and variation data. V1.3.0 V1.0.0 Specification Documentation Endpoint Read File Formats (SAM/BAM/CRAM) Specifications for storing next-generation sequencing read data. V3.0.0 V3.0.0 Implementation Example of Usage Variation File Formats (VCF/BCF) The specifications for Variant Call Format Files (VCF) and its binary counterpart BCF. V4.0.0 V2.0.0 V4.0.0 V2.0.0 Implementation Example of Usage Crypt4GH v1.0 Enables direct byte-level compatible random access to encrypted genetic data stored in community standards (e.g. CRAM, VCF) V1.0 V1.0 Specification Documentation Endpoint refget API Enables access to reference sequences using an identifier derived from the sequence itself. V1.2.6 NA Specification RNAget API v1 Provides a means of retrieving data from several types of RNA experiments including (i) feature-level expression data from RNA-seq type measurements and (ii) coordinate-based signal/intensity data similar to a bigwig representation via a client/server model. V1.0.0 NA Documentation Discovery Beacon v2 Supports discovery of genomic variants, phenotypes, and individuals V1.0.1 V0.3 Web UI API Source Code Service Info API v1 The Service Info API is an endpoint for describing GA4GH service metadata, designed for extension and inclusion in other APIs. Service info is used to describe a single service, while Service Registry is used to describe multiple services. V1.0.0 NA Documentation Service Registry API v1 provides information about other GA4GH services, primarily for the purpose of organizing services into networks or groups and service discovery across organizational boundaries. V1.0.0 NA Documentation Data Use Researcher Identities Data Use Ontology (DUO) Allow users to semantically tag genomic datasets with usage restrictions, allowing them to become automatically discoverable based on a health, clinical, or biomedical researcher’s authorisation level or intended use. 2021-02-23 2021-02-23 Specification Documentation Endpoint Authentication & Authorization Infrastructure (AAI) The GA4GH AAI specification leverages OpenID Connect (OIDC) Servers for use in authenticating the identity of researchers desiring to access clinical and genomic resources from data holders adhering to GA4GH standards, and to enable data holders to obtain security-related attributes of those researchers. V1.2.0 V1.2.0 API URI: ega.ebi.ac.uk:8443 Documentation Repository Researcher IDs (passport, visa) Specify the collection of researchers that may access a dataset at any given time, and the credentials they must supply. V1.0.1 V1.0.1 Specification Documentation Endpoint Cloud Tool Registry Service API TRS is a standard API for exchanging tools and workflows to analyze, read, and manipulate genomic data. V2.0.1 NA Documentation Repostiory Data Repository Service API ​DRS API is a standard for building data repositories and adapting access tools to work with those repositories, works with other approved APIs from the GA4GH Cloud Work Stream to allow researchers to discover algorithms across different cloud environments and send them to datasets they wish to analyse. V1.0.3 NA Documentation Repostiory Workflow Execution Service API This API lets users run a single workflow (defined using CWL or WDL) on multiple different platforms, clouds, and environments, and be confident that it will work the same way. The API provides methods to request that a workflow be run, pass parameters to that workflow, get information about running workflows, and cancel a running workflow. V1.0.1 NA Documentation Repostiory Genomic Knowledge Standards Variation Representation v1 Provides a flexible framework of computational models, schemas, and algorithms to precisely and consistently exchange genetic variation data across communities. V1.3.0 EGA team is contributing to including it in in Beacon v2 Specification and Elixir Reference Implementation Documentation Repostiory Clin/ Pheno Data Capture Phenopackets Provides information models with different levels of complexity to enable high level clinical phenotype information as well as deep clinical phenotype information to be exchanged. V2.0.0 Included in Ongoing Submissions EGA team is contributing to including it in in Beacon v2 Specification and Elixir Reference Implementation Documentation Repostiory Driver Project The EGA, jointly coordinated by the EBI and the CRG, was announced, in 2017, to be one of the 15 Driver Projects for GA4GH. Driver Projects are international genomic data initiatives, focussed on real projects and challenges that will guide the development efforts in order to accelerate and enable completely responsible and standarised data sharing by 2022. All chosen Driver Projects make a cross-sectional effort by playing an important role across the different workstreams. Thomas Keane, Jordi Rambla, Mallory Freeberg, and Aina Jené have been named Driver Project Champions for the EGA. All Driver Project Champions will be leading this ambitious initiative for the following years.

  Documentation about/projects-and-funders/ga4gh

• SEARCH for Diabetes in Youth Study - Genetic Risk Score

  Genetic risk scores (GRS) quantify polygenic disease risk into a single measure and can aid in disease classification. GRS studies have focused primarily on adult populations of recent European ancestry. We aimed to assess the utility of GRS in classification of diabetes type among racially/ethnically diverse youth in the United States. We used data from SEARCH baseline visits and follow up visits for which key data elements were available. 2260 participants are included. Phenotypic Data to be submitted here include: Self-reported sex, race and ethnicity Diabetes type determined by provider Etiologic diabetes type T1D (antibody positive, or antibody negative/missing and insulin sensitive) T2D (antibody negative and insulin resistant) Diabetes duration (years) Age at diagnosis (years) Measures from baseline, SEARCH 3 (follow-up) and SEARCH 4 (follow-up): Age Height Weight Waist circumference HbA1c Fasting/non-fasting glucose C-peptide Triglycerides HDL LDL Systolic Blood Pressure Diastolic Blood Pressure Measures from SEARCH 3 and 4:Arterial stiffness as characterized by PWVRetinopathy Measures from SEARCH 4 only: LV structure and diastolic function measurements from echocardiogram GAD autoantibody IAD autoantibody ZnT8 autoantibody We performed genotyping using the Illumina Multi-Ethnic Global Array (MEGA) array with 1,697,069 genotyped variants including 748,291 with minor allele frequency <0.01. Genotyping and preliminary quality control checks were performed at the Colorado Center for Personalized Medicine. After additional quality control, 2,238 samples and 900,743 variants remained for analyses. Samples genotyped on the MEGA array were categorized using SEARCH etiologic type and consisted of predominantly type 1 diabetes cases (n=2,051) but also those with other diabetes (n=133 type 2 diabetes, n=52 other diabetes including monogenic diabetes; genetic confirmation with either a genetic clinical test or test performed as an ancillary study to SEARCH). The median reported age at DNA collection was 11.2 years (interquartile range 7.6 – 14.1) with a minimum age of 1.9 years and maximum of 21.9 years. We used additional data genotyped on the Affymetrix 500K imputation scaffold chip with 239,279 genotyped variants. This cohort consisted of predominantly type 2 diabetes cases (n=417) but also those with type 1 (n=104), and other diabetes types (n=16). After additional quality control, 537 samples and 235,967 variants remained. The median reported age at collection was 11.2 years (quartile range 8.1 – 14.2) with a minimum of 2.0 years and a maximum of 21.1 years. About 100 type 2 diabetes cases were also genotyped using the MEGA chip to ensure concordance between the data sets and facilitate strand alignment between the two chips before genotypic imputation. The data sets had n=230,228 genotyped variants in common and concordance between the genotypes was high (mean correlation r2 for SNPs used in GRS=0.95). We used the 1000 Genomes reference panel to impute each data set separately, resulting in a total of 34.5M and 27.8M well-imputed variants (r2>0.8) for the MEGA and Affymetrix data sets respectively. We combined high quality imputed variants for analysis.

  Study phs002703

• Incentives and Case Management to Improve Cardiac Care: Healthy Lifestyle Program (HeLP)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this study.Objectives: The HeLP study assessed how early case management, financial incentives contingent on cardiac-rehabilitation attendance, or both impacted adherence to cardiac rehabilitation among patients with lower socioeconomic status (SES) who had a cardiac-rehabilitation-qualifying diagnosis. Background:Cardiovascular disease (CVD) is the leading cause of death in the United States. Regular attendance at cardiac rehabilitation (CR) is the number one recommendation for patients who have experienced a recent cardiac event. CR is a secondary prevention outpatient program involving an individually tailored structured exercise program along with counseling and encouragement regarding lifestyle changes to reduce the recurrence of major cardiac events.Despite the benefits of CR attendance, enrollment and adherence to the program are low. This is particularly true of individuals of lower socioeconomic status (SES), who also generally suffer a higher burden from CVD on account of higher-risk cardiac profiles. As these profiles are the result of modifiable behavior targeted by CR (i.e., smoking, obesity, lack of physical activity), methods of increasing CR attendance among this population are necessary.Case management and financial incentives contingent on CR attendance are two potential strategies for addressing this issue. Previous studies have shown how trained case managers can support and assist patients with attending CR and improving their cardiac health, and how financial incentives can promote various types of health-related behavior. The purpose of the present study was to evaluate how these two interventions, individually and in tandem, fared at improving CR adherence among individuals of lower SES specifically. Participants:A total of 314 participants were screened, and 209 were randomized. All consented to have their data shared for research purposes. Design:Eligible patients were approached either while still in the hospital or during initial visits to CR. After obtaining informed consent, clinical and demographic characteristics (i.e., age, sex, education, race and ethnicity, smoking status, and CR-qualifying diagnosis) and depressive symptoms were collected. Participants then were randomized 2:3:3:3 to usual care (UC), case management starting in hospital (CM), financial incentives for attending CR (FI), or financial incentives plus case management (FICM). For all participants regardless of condition, an appropriate referral for CR was confirmed after randomization. Over the course of the study participants completed three assessments – one at intake, one after four months, and one after one year. Clinical (i.e., cardiorespiratory fitness, body composition, and cardiac-related quality of life) and sociocognitive (i.e., Beck Depression Inventory, Achenbach System of Empirically Based Assessment, and Behavior Rating Inventory of Executive Function) measures were obtained at each assessment. Participants randomized to the UC condition were contacted weekly by study staff for adverse event checks, but received no additional intervention. Participants randomized to the CM condition were immediately assigned a case manager. Case managers met with their participants, usually within 24 hours of consent while they were still in the hospital, to introduce themselves during an initial check-in. Within the first week of consent they completed a longer, more thorough initial needs assessment with their participant and established behavioral goals. For the next 16 weeks, case managers met with their participants at least once a week, typically over the phone, to discuss progress on these goals and address any problems or barriers that had arisen. Case managers also were available via phone outside of these regular meetings during normal working hours and Saturday mornings. Participants randomized to the FI condition could earn money for completing an initial CR orientation and attending CR sessions. Twenty dollars could be earned for completing the CR orientation session. CR attendance was reinforced on an escalating schedule starting at $10. Payments increased by $2 for each successive session attended, and capped out at a maximum of $40 per session. Unexcused absences resulted in the incentives for that session not being earned, and the potential earnings for the next scheduled session being reset to $10. Successful participation of two consecutive sessions following the reset resulted in the incentives being returned to the amount prior to the reset. In total, participants could earn $1220 for attending the initial orientation and all 36 sessions of CR. The primary outcome of interest was the percentage of participants who completed at least 30 sessions of CR. Secondary outcomes included the number of sessions completed, cardiorespiratory fitness (peak VO2 and estimated metabolic equivalents (METs)), body composition (waist circumference and BMI), depression scores, and both general and cardiac-related qualify of life. Conclusions:The two interventions involving financial incentives (i.e., financial incentives alone and financial incentives plus case management) significantly improved CR adherence compared to usual care. Subsequent analyses revealed that the combination of financial incentives and case management led to greater improvements in CR attendance than financial incentives alone.

  Study phs003737

• High Density SNP Association Analysis of Lung Cancer

  This research builds upon an extensive resource of a case-control study that has been ongoing at the UT MD Anderson Cancer Center since 1991. To identify risk variants for lung cancer, we conducted a genome-wide association study. Cases are newly diagnosed, histologically-confirmed patients presenting at MD Anderson Cancer and who had not previously received treatment other than surgery. Controls are healthy individuals seen for routine care at Kelsey-Seybold Clinics, the largest physician group-practice plan in the Houston Metropolitan area. This lung GWAS led to the identification of a susceptibility locus for lung cancer at 15q25.1. We used data from 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas in the discovery followed by the replication of the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, were significantly associated with risk of lung cancer with combined analysis yielded odds ratios of 1.32 (P < 1X10-17) for both SNPs. These two SNPs mapped to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5. (Nat Genet. 2008 May;40(5):616-22. PMID:18385676)

  Study phs000753

• Population Genetic Testing and SERPINA1 Sequencing Identifies Unidentified Alpha-1 Antitrypsin Deficiency Alleles and Gene-Environment Interaction with Hepatitis C Infection

  Design and aims: Data were available through an institutional effort to combine de-identified electronic health records (EHR) data with genomic information from a DNA biobank. The design of this work was a retrospective cohort study in which we investigated the rates of liver transplantation and hepatitis C infection as it relates to genotype risk for alpha-1 antitrypsin deficiency (AATD). We used regression analysis to look for relationships between these risks and outcomes. This led to further investigation of environmental exposures and phenotypes as it related to the underlying genotypic risk. Population information: The cohort consisted of 72,027 individuals of European ancestry for whom genotype and EHR data were available. Molecular technologies employed: Genome-wide genotyping was previously performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content (referred to as the Vanderbilt University Medical Center BioVU MEGAEX). Individuals' AATD-related alleles were inferred from the genotyping data. Principal findings of the study: Liver transplantation was associated with presence of the Z AATD allele and with hepatitis C infection. There was a significant interaction between AATD genotype groups and hepatitis C infection as it related to liver transplantation. Data available through dbGaP: Inferred AATD genotype status, sex, age, length of EHR in years, presence/absence of AATD clinical diagnosis, liver transplant status, and hepatitis C infection status.

  Study phs003297

• GWAS for Genetic Determinants of Bone Fragility in European-American Premenopausal Women

  Osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength. Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is the most important determinant of bone strength and fracture risk. Between 60 and 80% of the variance of BMD of adult Caucasian women is due to heritable factors. Final BMD is a function of peak bone mass attained during young adulthood and the subsequent rate of bone loss, which occurs as a result of both post-menopausal estrogen loss and aging. The evidence for a genetic contribution to rate of loss in BMD is substantially weaker than that for peak BMD. Therefore, we have focused our sample collection on the recruitment of premenopausal women, in whom we have sought to identify the genes influencing peak BMD at the spine and hip, the two major skeletal sites of osteoporotic fracture. The primary goal of this study is to identify genes that affect peak BMD in premenopausal women. Identification of these genes may: 1) lead to molecular tests that predict risk of osteoporosis and allow institution of early preventive measures; 2) provide insight into basic bone cell biology and other factors that affect peak BMD; and 3) provide molecular targets for therapeutic agents to increase BMD.

  Study phs000138

• BrainCloud: Data from human postmortem brain procurement for the neuropathology section

  This study explores the temporal dynamics and genetic control of transcription and DNA methylation in the human dorsolateral prefrontal cortex in postmortem tissue. This study examines 269 subjects for gene expression (version 1) and 108 subjects for DNA methylation (version 2). The subjects are normal controls without neuropathological and neuropsychiatric diagnosis and range in age from fetal weeks 14-20 through old age (>80). We discover fast changes in gene expression occurring during early brain development. Later in life, the changes are considerably slower. Many genes reverse pattern of expression between fetal and early postnatal development. We identify thousands of strong associations of SNPs with gene expression. We examine DNA methylation in ~14,500 genes at ~27,000 CpG loci focused on 5' promoter regions. The fastest changes in DNA methylation also occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes. DNA for genotyping was obtained from the cerebella and applied to either Illumina 650K or 1 million BeadArrays - only genotypes common to both platforms are analyzed here. Genotypes were called using BeadExpress software. Doi: 10.1038/nature10524 Nature, 478:519-524, 2011; doi:10.1016/j.ajhg.2011.12.020, AJHG 90, 1-13, Feb 10, 2012. The methylation data can be downloaded at: BrainCloud.

  Study phs000417

• Genome-Wide Association Study of Heparin-Induced Thrombocytopenia

  Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome. Genetic associations were investigated in a cohort of functional assay-confirmed HIT cases, antibody-positive (function assay-negative) controls, and antibody negative controls. Both PF4-specific enzyme-linked immunosorbent assay (ELISA) and serotonin release assay (SRA) were positive in every HIT case. GWAS genotyping was performed at the Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences (IMS). All samples in the discovery and replication cohorts were genotyped using the lllumina® Infinium HumanOmniExpressExome BeadChip, which contains 958,497 markers, including 273,000 functional exonic markers. Quality control was accomplished using sample and marker call rate ≥98%, sex mismatch, duplicate concordance, and removal of related samples through identity by descent. Genomic imputation was performed for samples using Minimac4 and the phase3 v5 reference panel data from the 1000 genomes project. The primary GWAS analysis used multivariable logistic regression assuming an additive genetic model with functional assay-confirmed case status as the outcome. Both PF4/heparin antibody negative and antibody positive controls were considered controls in the primary analysis. Logistic regressions were used to generate odds ratios and 95% confidence intervals (95%CIs) after adjustment for age, sex, and first three principal components.

  Study phs002863

• The Bangladesh Environmental Enteric Dysfunction (BEED) Study

  Environmental enteric dysfunction (EED), a sub-acute inflammatory condition of the small intestinal mucosa of unclear etiology, has been associated with a variety of environmental exposures and host factors and is implicated in growth faltering. Linear growth faltering usually occurs within the first two years of life and in most of the cases is irreversible demanding early diagnosis for treatment to be successful. The objectives of 'The Bangladesh Environmental Enteric Dysfunction Study (BEED)' are to investigate role of EED in malnutrition, examine the biology of EED to identify common biological pathways for potential interventions, to validate a system for histological scoring for EED and test the effectiveness of nutritional interventions in improving the growth parameters in children with stunting and or EED. In Bangladesh, participants are recruited from two age groups; a child cohort and a malnourished an adult cohort. In addition, two control groups are recruited for comparison consisting of a) children that are undergoing endoscopy as a part of their clinical care at the University of Virginia Health system (UVAHS) and b) an adult well-nourished control group recruited from the Gastroenterology Outpatient Department of Dhaka Medical College and Hospital in Bangladesh. The description of the study design and procedures of the study can be obtained from Mahfuz M, Das S, Mazumder RN, et al., 2017, PMID: 28801442.

  Study phs001891

• Investigating Host Genetic Risk Factors for Tuberculosis in Highly Endemic South African Populations

  It is apparent from our recent population genetic and admixture mapping work 1–3 that a substantial part of the ancestral input into the South African Coloured (SAC) population is from the San or Khoe groups, which are not well represented in publicly available genetic databases. It is a reasonable assumption that the SAC population in the Western Cape may have derived more genetic input from the present KhoeSan population in the Northern Cape than the San residing in Namibia. It was concluded by our group that it is indeed the southern African KhoeSan group, the ≠Khomani, that best represent the KhoeSan contribution seen in the SAC 4. More recently, it has been shown that there are ancestry related increases in TB susceptibility, especially with increased Bantu-speaking African and KhoeSan ancestry 5. We aim to elucidate the epidemiological and human-host genetic risk factors for TB and the immunological pathways modulating TB infection. The proposed sub-study will enroll people evaluated for TB at Northern Cape community health clinics and their contacts from their households and/or community. We will conduct a demographic interview, collect saliva, which will be used for genetic analysis, and blood to determine latent TB infection status and capture immunological responses to mycobacterial infections at the cellular level and RNA sequencing.

  Study EGAS00001007850

• Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma

  Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes, and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

  Study EGAS00001002443

• An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors

  We undertook an empirical approach to dissect the tumor microenvironment by developing a bulk tumor dissection algorithm, DisHet, and leveraging RNA-Seq data of tumorgrafts (patient-derived tumors implanted in mice), in which only the tumor cell component expands. We found that approximately 65% of previously defined immune signature genes are not abundantly expressed in the Renal Cell Carcinoma (RCC) microenvironment, and we identified more than two times as many novel immune/stromal transcripts. By using refined immune/stroma-specific genes and genomics, electronic medical record data and imaging data of 1084 RCC patients, we discovered a highly-inflamed pan-RCC subtype enriched for Treg cells, NK cells, Th1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. This inflamed subtype (IS) is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. Interestingly, IS is correlated with systemic manifestations of inflammation in patients such as thrombocytosis and anemia, whose pathogenesis were poorly defined and have been predictors of poor prognosis in RCC. Indeed, we discovered that IS is a strong predictor of poor survival. Lastly, our analyses show that tumor cells may drive stromal immune response. Overall, these data provide a missing link between the tumor cells, the tumor microenvironment, and systemic factors.

  Study EGAS00001002786

• Prognostic relevance of microenvironmental factors CD163 and CD8 combined with EZH2 and chromosome 18 gain in a validation cohort of follicular lymphoma patients of the Lunenburg Lymphoma Biomarker Consortium

  Background: In follicular lymphoma (FL), studies addressing the prognostic value of microenvironment-related immunohistochemical (IHC) markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium (LLBC) performed a validation study for published markers. Methods: To maximize sensitivity, an end-of-spectrum design was applied for 122 uniformly immunochemotherapy-treated FL patients retrieved from international trials and registries; early failure (EF): progression or lymphoma-related death <2 years versus long remission: response duration of >5 years. IHC staining for T-cells and macrophages was performed on tissue microarrays from initial biopsy and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. Results: 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (p=0.006), gain of chromosome 18 (p=0.002), low percentages of CD8+ cells (p=0.011) and CD163+ areas (p=0.038) were associated with EF. No significant differences in other markers were observed, thereby refuting previous claims on their prognostic significance. Conclusion: Using an optimized study design, this LLBC study validates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of EF to immunochemotherapy in FL.

  Study EGAS00001002049

• Transcriptional and DNA binding profiling of CEBPE in REH acute lymphoblastic leukaemia cells using shRNA RNA-Seq and ChIP-Seq

  ChIP-Seq - CEBPE - REH. The ETV6/RUNX1 translocated acute lymphoblastic leukaemia cell line REH was used to perform ChIP-Seq using a CEBPE antibody. Cells were fixed in 1% formaldehyde for 10mins, prior to preparation of chromatin using Active Motif Express ChIP-IT. 2ug of antibody (anti CEBPE Atlas Antibodies HPA002928)was added to 25ug of chromatin O/N at 4C with rotation. Duplicate reactions were pooled and purified. 10ng of ChIPd and input DNA used for Illumina NGS preparation (NEBNext ChIP-Seq Library kit; New England Biolabs), CEBPE and Input DNA ChIP samples were sequenced on a MiSeq using 150bp Kit v3 paired end and a HiSeq 2500 using 2x101 version 4 paired end (Illumina) respectively. Reactions performed in duplicate. shCEBPE RNA-Seq - REH. REH cells were lentivirally transduced with a pTRIPZ shRNA vector for transcriptional profiling of CEBPE. Two controls (empty and non-targeting) and two CEBPE shRNAs (V3THS_150517(A13), V3THS_404312(G3) Dharmacon, GE) were transduced into REH cells. Cells were treated with 1ug/ml doxycyclin for 144hrs and total RNA purified. Libraries were prepared using NEBNext Ultra II Directional RNA Library Prep Kit and sequenced on an Illuimna HiSeq 2500 using 2x101 version 4 paired end chemistry. 3 biological replicates of each samples were prepared.

  Study EGAS00001002877

• Bulk-tissue RNA-sequencing paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from post-mortem neuropathologically-confirmed control individuals.

  Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.

  Study EGAS00001006380

• Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target

  High-risk sarcomas, such as metastasized and relapsed Ewing and CIC-rearranged sarcomas, currently lack effective curative systemic treatment options. Precision medicine approaches offer hope and among them ex vivo drug response profiling of patient-derived tumor cells emerges as a promising novel tool to identify effective drugs for individual patients. Here, we established ex vivo culture conditions to propagate Ewing and CIC::DUX4-sarcomas as tumoroids in a co-clinical manner. These models retained their original molecular and functional characteristics, including recurrent ARID1A mutations, and serve as tumor avatars suitable for large-scale drug testing. Indeed, screening a large drug library on a small living biobank of such tumors not only revealed distinct response differences between the two entities, but also identified an exceptional dependency of CIC::DUX4-sarcoma cells on MCL1. Mechanistically. MCL1 was identified as a direct target gene of the CIC::DUX4 fusion protein. Genetic and pharmacological inhibition of MCL1 induced rapid apoptosis in CIC::DUX4-sarcoma cells and inhibited tumor growth in a xenograft model. Thus, MCL1 represents a potential novel therapeutic target for CIC::DUX4-sarcoma. Overall, our study highlights the feasibility of co-clinical drug response profiling for individual sarcoma cases and suggests that prospective tests, to evaluate its clinical benefit are highly warranted.

  Study EGAS00001008039

• NHLBI TOPMed: The Genetics and Epidemiology of Asthma in Barbados

  Asthma is a complex disease where the interplay between genetic factors and environmental exposures influences susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry. The baseline prevalence of asthma in Barbados is high (~20%), and from admixture analyses, we have determined that the proportion of African ancestry among Barbadian founders is similar to U.S. African Americans, rendering this a unique population to disentangle the genetic basis for asthma disparities among African ancestry populations in general. We therefore performed whole genome sequencing on 1,100 individuals from the Barbados Genetics of Asthma Study (BAGS), in order to generate additional discovery of rare and structural variants that may control risk to asthma.

  Study phs001143

• Low Density Genotyping from the Fragile Families and Child Wellbeing Study

  The Fragile Families and Child Wellbeing Study (FFCWS) is based on a stratified, multistage sample of 4898 children born in large U.S. cities (population over 200,000) between 1998 and 2000, where births to unmarried mothers were oversampled by a ratio of 3 to 1. This sampling strategy resulted in the inclusion of a large number of Black, Hispanic, and low-income families. The project “Low Density Genotyping from the Fragile Families & Child Wellbeing Study” uses saliva collected from a subset of FFCWS children at Year 9 and from teens at Year 15 to examine genetic variation using a genome-wide assay (Illumina PsychChip). In addition to the genotype data, a limited set of self reported and anthropomorphic measures are included.

  Study phs002417

• BPH Tissues for Cell Culture and Analysis - A Patient-Derived Xenograft Model Using Benign Prostatic Tissues

  Our goal was to establish and characterize a patient-derived xenograft model for benign prostatic hyperplasia (BPH) using human benign prostatic tissues. Characterization of the model was done by histology, immunohistochemistry, proteomics, and transcriptome analysis (RNAseq). The RNAseq data will be deposited in dbGaP. Subjects were undergoing prostatectomy for prostate or bladder cancer, with concurrent BPH, and consented to the use of surplus tissue for research studies. The RNAseq studies included 6 patients. Phenotypic data include patient age, sex, prostate size, serum prostate-specific antigen (PSA) level, and international prostate symptom score (IPSS). Sequencing was done on an Illumina NovaSeq 6000, and data were analyzed using Kallisto. Data are submitted as raw sequencing (fastq) files.

  Study phs003692

• The PRIME-AIR Study: Positive End-Expiratory Pressure, Recruitment, Incentive Spirometry, Muscle Relaxant Optimization, Preoperative Education, Postoperative Early Ambulation, Individualized, and Reinforced

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.The PRIME-AIR study ("Positive end-expiratory pressure, Recruitment, Incentive spirometry, Muscle relaxant optimization, preoperative Education, postoperative early Ambulation, Individualized, and Reinforced") was a prospective multi-center randomized controlled pragmatic trial, with a blinded assessor, to compare post-operative pulmonary complications (PPCs) in patients with an individualized anesthetic-centered intervention (including individualized mechanical ventilation positive end-expiratory pressure (PEEP) management to maximize respiratory system compliance and minimize driving pressures, a neuromuscular agent and subsequent reversal, and post-operative lung expansion and early mobilization) versus usual care.

  Study phs003926

• RNA sequencing of CAR-T cells with CD38-CD73-Tim-3-HLA-DR+ phenotype and others in infusion products of tisagenlecleucel for B-cell precursor acute lymphoblastic leukemia

  We enrolled 19 patients with BCP-ALL who took tisagenlecleucel, and infusion products and patient samples were obtained before and after CAR-T infusion. Single-cell analysis by CyTOF revealed that central memory CAR+ T cells increased in long-term responders, whereas PD-1highCD38highCXCR3+ effector CAR+ T cells were enriched in relapsed patients after CAR-T infusion. Furthermore, in long-term responders, CAR+ T cells obtained from infusion products were enriched with CD38-CD73-Tim-3-HLA-DR+ phenotype, and characterized by decreased ability to produce adenosine, and they showed more memory-like transcriptomic characteristics. We elucidated the characteristics of tisagenlecleucel related to a durable response, which could contribute to improving the clinical outcome.

  Study JGAS000760